Methods for preparing d-threo methylphenidate using diazomethane, and compositions thereof

ABSTRACT

Novel methods and systems for producing a substantially pure d-threo stereoisomer of methylphenidate or a salt thereof are provided. In particular, methods and systems for producing d-threo-methylphenidate hydrochloride in pure stereoisomeric form from d-threo-ritalinic acid hydrochloride using diazomethane are described. The described methods can be performed on a large scale, and thus provide d-threo methylphenidate or a salt thereof, and particularly the hydrochloride salt of d-threo-methylphenidate, in stereoisomerically pure form and in large quantities from a single batch reaction. Also described are novel compositions of d-threo methylphenidate hydrochloride.

FIELD OF THE INVENTION

The present invention relates to a method for producing a substantiallypure d-threo stereoisomer of methylphenidate or a salt thereof byconverting a carboxylic acid group on a substantially pure d-threostereoisomer of ritalinic acid or a salt thereof to an ester group usingdiazomethane, and compositions thereof. In particular, the presentinvention relates to a method for producing substantially pured-threo-methylphenidate hydrochloride by reacting substantially pured-threo-ritalinic acid hydrochloride with diazomethane. Methodsaccording to the present invention can be used to produce the targetcompound in large quantities.

BACKGROUND OF THE INVENTION

Substituted piperidine compounds have been used in the treatment of manynervous system disorders. One particular substituted piperidine compoundproven useful in treating central nervous system disorders isdexmethylphenidate, which is often prescribed to control symptoms ofattention deficit hyperactivity disorder (ADHD).

Dexmethylphenidate, also referred to as d-threo-methylphenidate and(2R,2′R)-(+)-threo-methylphenidate, is the d-threo stereoisomer ofmethylphenidate. Methylphenidate exists in four stereoisomeric forms,d-threo, l-threo, d-erythro and 1-erythro. d-threo-methylphenidate and1-threo-methylphenidate are enantiomers, whereas1-erythro-methylphenidate and d-erythro-methylphenidate are enantiomers.However, preparing and isolating dexmethylphenidate in its purestereoisomeric form, i.e., the d-threo stereoisomer, has proven to bedifficult.

The preparations of enantiomerically pure dexmethylphenidatehydrochloride were reported by R. Rometsch in U.S. Pat. Nos. 2,838,519and 2,957,880. According to the methods described by Rometsch,enantiomerically pure 1-erytho-2-phenyl-2-(2-piperidyl)acetamide wasfirst obtained by resolution of a racemic mixture oferythro-2-phenyl-2-(2-piperidyl)acetamide with d-(±)-tartaric acid in96% ethanol. The enantiomerically pure1-erythro-2-phenyl-2-(2-piperidyl)acetamide was epimerized in aqueouspotassium hydroxide to the d-threo-2-phenyl-2-(2-piperidyl)acetamidestereoisomer. d-threo-methylphenidate hydrochloride was then obtainedupon hydrolysis and esterification ofd-threo-2-phenyl-2-(2-piperidyl)acetamide.

The initial approach described by Rometsch was further optimized byKhetani et al. in PCT Patent Application Publication No. WO 98/52921 andRamaswamy et al. in U.S. Pat. No. 5,965,734. Resolution of a racemicmixture of erythro-2-phenyl-2-(2-piperidyl)acetamide with d-(±)-tartaricacid in methanol afforded a 40% yield of1-erythro-2-phenyl-2-(2-piperidyl)acetamide. Epimerization of1-erythro-2-phenyl-2-(2-piperidyl)acetamide with potassium tert-butoxidein toluene at 70° C. furnished d-threo-2-phenyl-2-(2-piperidyl)acetamidein 85% yield. d-threo-2-phenyl-2-(2-piperidyl)-acetamide was convertedto d-threo-methylphenidate hydrochloride upon treatment withconcentrated sulfuric acid in refluxing methanol and hydrochloride saltin 80% yield.

Further, several methods have been reported for enriching theenantiomeric purity of dexmethylphenidate, with the first method beingreported in 1987 by Patrick et al. in J. Pharm. Exp. Ther. (1987) 241,152-158, by crystallization of dexmethylphenidate from a mixture ofmethanol and ether. Novartis also reportedly increased the enantiomericpurity of dexmethylphenidate hydrochloride from 80% enantiomeric excess(e.e.) to greater than 98% e.e. by recrystallization from a 1:1.7 (v/v)mixture of methanol and t-butyl methyl ether (M. Prashad et al.,Tetrahedron: Asymmetry (1998) 9, 2133-2136). PCT Patent ApplicationPublication No. WO 98/25902 also reports an enrichment of theenantiomeric purity of dexmethylphenidate hydrochloride from this samesolvent mixture. Although such attempts to enrich the enantiomericpurity of dexmethylphenidate hydrochloride by recrystallization doprovide enantiomerically pure compound, recrystallization results inloss of yield and is not desirable for use with reactions that areperformed on a large scale to obtain large quantities of the desiredproduct.

An alternative approach to synthesizing enantiomerically pured-threo-methylphenidate hydrochloride using an enantiomerically purestarting material, d-pipecolic acid, was reported by Thai et al. in J.Med. Chem. (1998) 41, 591-601. Enantiomerically pure d-pipecolic acidwas obtained in 37% yield by recrystallization of the diastereomerictartrate salt, followed by the separation of the desired amino acid fromtartaric acid by ion-exchange chromatography. d-pipecolic acid wasprotected with a BOC group to afford N—BOC-d-pipecolic acid in 97%yield. The key amino ketone was prepared from N—BOC-d-pipecolic acid intwo steps involving its conversion to the N-methoxy-N-methyl amide,followed by a reaction with the amide with phenyllithium. The aminoketone underwent a Wittig olefination with methyltriphenylphosphoniumbromide in the presence of potassium tert-butoxide to give the alkene inhigh yield. The transformation of the obtained alkene to the desiredalcohol as a racemic mixture of threo-stereoisomers via ahydroboration/oxidation reaction was critical to introducing the secondstereogenic center. Hydroboration with BH₃-THF gave a 72:28 mixture ofthreo and erythro isomers, respectively, from which the threo alcoholwas isolated in 64% yield after chromatography. Oxidation of the threoalcohol with pyridinium dichromate (PDC) in dimethylformamide (DMF)followed by esterification of the resulting acid with diazomethane, andN—BOC group deprotection with 3 N methanolic hydrochloric acid furnishedd-threo-methylphenidate hydrochloride in 67% yield afterrecrystallization from a mixture of ethanol and ether.

However, all of the aforementioned methods for obtainingdexmethylphenidate in its pure enantiomeric form require eitherrecrystallization from a mixture of stereoisomers, or a large number ofsynthetic steps, both of which result in reduced yields. Thus, there isa need for improved methods of preparing dexmethylphenidate in its pureenantiomeric form and in high yield. Preferably, such methods are alsoadaptable to production on a large scale, which would have the advantageto provide a method for obtaining dexmethylphenidate in its pureenantiomeric form and in large quantities from a single reaction.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to methods for preparing d-threomethylphenidate in enantiomerically pure form in large quantities ascompared to other methods known in the art for preparing such compounds.In particular, the present invention relates to methods for preparing asubstantially pure d-threo methylphenidate or a salt thereof, andpreferably d-threo-methylphenidate hydrochloride, by a reaction thatemploys diazomethane. Methods according to the present invention can beperformed on a large scale, and thus provide stereoisomerically purecompound in large quantities from a single batch reaction.

In one general aspect, the present invention relates to a method forpreparing a substantially pure d-threo stereoisomer of methylphenidaterepresented by formula (I):

or a salt thereof represented by formula (I-a):

the method comprising:

-   -   (i) obtaining a first solution comprising an aqueous solution of        an inorganic base and a water miscible solvent;    -   (ii) obtaining a second solution comprising an        N-methyl-N-nitroso amine of formula (IV):

-   -   -   in a water immiscible organic solvent;

    -   (iii) adding the second solution to the first solution, thereby        generating diazomethane; and

    -   (iv) reacting a substantially pure d-threo stereoisomer of        ritalinic acid represented by formula (II):

-   -   or a salt thereof represented by formula (II-a):

-   -   -   with the diazomethane generated in step (iii) to obtain the            substantially pure d-threo stereoisomer of methylphenidate            or salt thereof,            wherein R¹ represents a phenyl group; R² represents a member            selected from the group consisting of

R₃ represents a hydrogen atom, an alkyl group having one to four carbonatoms, or a nitro group; R₄ represents a hydrogen atom or an alkyl grouphaving one to four carbon atoms; and X represents fluorine, chlorine,bromine, iodine, or tetrafluoroborate.

In another general aspect, the present invention provides a method forpreparing substantially pure d-threo-methylphenidate hydrochloride, themethod comprising:

-   -   (i) obtaining a first solution comprising an aqueous solution of        an inorganic base and a water miscible solvent;    -   (ii) obtaining a second solution comprising an        N-methyl-N-nitroso amine of formula (IV):

-   -   -   in a water immiscible organic solvent;

    -   (iii) adding the second solution to the first solution, thereby        generating diazomethane; and

    -   (iv) reacting substantially pure d-threo-ritalinic acid        hydrochloride with the diazomethane generated in step (iii) to        obtain the substantially pure d-threo-methylphenidate        hydrochloride,

wherein R² represents a member selected from the group consisting of

R₃ represents a hydrogen atom, an alkyl group having one to four carbonatoms, or a nitro group; and R₄ represents a hydrogen atom or an alkylgroup having one to four carbon atoms.

In yet another general aspect, the present invention relates to a systemfor producing a substantially pure d-threo stereoisomer ofmethylphenidate represented by formula (I):

or a salt thereof represented by formula (I-a):

the system comprising:

-   -   (i) a reaction chamber comprising:        -   (a) a generator portion comprising an inlet, and holding an            aqueous solution comprising an inorganic base and a water            miscible solvent, and        -   (b) a receiver portion connected to the generator portion by            a condenser, the receiver portion holding a substantially            pure d-threo stereoisomer of ritalinic acid represented by            formula (II):

-   -   -   or a salt thereof represented by formula (II-a):

and

-   -   (ii) a solution of an N-methyl-N-nitroso amine of formula (IV):

-   -   -   in a water immiscible organic solvent,            wherein the generator portion is maintained at a temperature            sufficient to vaporize the organic solvent and any            diazomethane that is formed upon introduction of the            solution of the N-methyl-N-nitroso amino of formula (IV)            into the generator portion via the inlet; R¹ represents a            phenyl group; R² represents a member selected from the group            consisting of

R₃ represents a hydrogen atom, an alkyl group having one to four carbonatoms, or a nitro group; and R₄ represents a hydrogen atom or an alkylgroup having one to four carbon atoms; and X represents fluorine,chlorine, bromine, or tetrafluoroborate.

In a preferred embodiment, the present invention provides a system forproducing substantially pure d-threo-methylphenidate hydrochloride, suchthat the receiver portion of the reaction chamber holds substantiallypure d-threo ritalinic acid hydrochloride.

The invention also relates to compositions comprising substantially pured-threo-methylphenidate hydrochloride and an N-methyl species of d-threomethylphenidate hydrochloride. Preferably, the composition contains theN-methyl species of d-threo methylphenidate hydrochloride present inamount that is no more than 0.10% area based on peak area of a peakcorresponding to the N-methyl species as determined by high performanceliquid chromatography (HPLC) analysis relative to a total of 100% areabased on peak area of peaks corresponding to the substantially pured-threo-methylphenidate hydrochloride and N-methyl species thereof asdetermined by HPLC analysis.

Other aspects, features and advantages of the invention will be apparentfrom the following disclosure, including the detailed description of theinvention and its preferred embodiments and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Various publications, articles and patents are cited or described in thebackground and throughout the specification; each of these references isherein incorporated by reference in its entirety. Discussion ofdocuments, acts, materials, devices, articles or the like which has beenincluded in the present specification is for the purpose of providingcontext for the present invention. Such discussion is not an admissionthat any or all of these matters form part of the prior art with respectto any inventions disclosed or claimed.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention pertains. Otherwise, certain terms usedherein have the meanings as set forth in the specification. All patents,published patent applications and publications cited herein areincorporated by reference as if set forth fully herein. It must be notedthat as used herein and in the appended claims, the singular forms “a,”“an,” and “the” include plural reference unless the context clearlydictates otherwise.

The term “halogen,” as used herein, refers to an atom of fluorine,bromine, chlorine or iodine.

As used herein, the term “stereoisomers” refers to at least twocompounds having the same molecular formula and connectivity of atoms,but having a different arrangement of atoms in a three-dimensionalspace. A stereoisomer often, but not exclusively has a chiral carbonatom. As used herein, a “chiral carbon atom” is a carbon atom in whichfour different atoms or four different groups of atoms are attached.Compounds containing chiral carbon atoms typically, but not always,rotate the plane of polarized light, and are thus referred to as being“optically active.”

As used herein, the term “substantially pure stereoisomer” whenreferring to a compound that has multiple stereoisomers, means that thecompound exists as a single stereoisomer that is substantially free ofthe other stereoisomers of that compound, but not necessarily free ofother materials. As used herein, the term “substantially pure d-threostereoisomer,” when referring to a compound that has d-threo, l-threo,d-erythro, and 1-erythro stereoisomers, means that the compound existsas a d-threo stereoisomer that is substantially free of the 1-threo,d-erythro, and 1-erythro stereoisomers, but not necessarily free ofother materials. As used herein, “substantially pured-threo-methylphenidate” refers to the d-threo stereoisomer ofmethylphenidate that is substantially free of the 1-threo, d-erythro,and 1-erythro stereoisomers, but not necessarily free of othermaterials. As used herein, “substantially pure d-threo ritalinic acid”refers to the d-threo stereoisomer of ritalinic acid that issubstantially free of the 1-threo, d-erythro, and 1-erythrostereoisomers, but no necessarily free of other materials.

As used herein, a “water immiscible organic solvent” is any organicsolvent that forms a separate phase when contacted with water. A waterimmiscible solvent according to the invention can be an organic solventthat is fully immiscible with water, meaning that it is incapable ofbeing mixed with water to form a homogenous solution. A water immisciblesolvent according to the invention can also be an organic solvent thatis partially immiscible with water, as long as the organic solvent formsa second phase when contacted with water. Examples of water immiscibleorganic solvents that can be used in the invention include, but are notlimited to, ethers, such as diethyl ether, methyl ethyl ether, andmethyl propyl ether; alkanes, such as hexanes and heptanes; andhydrocarbon mixtures. Preferably, the water immiscible organic solventis an ether, and most preferably is diethyl ether.

As used herein, a “water miscible solvent” refers to any solvent thatcan form a homogeneous mixture with water when contacted with water. Fora solvent to be considered “water miscible,” there is little to no phaseseparation when the solvent is mixed with water. Examples of watermiscible solvents include, but are not limited to, water solublealcohols, such as methanol, ethanol, propanol; glycols, such as ethyleneglycol; acetone; acetonitrile; tetrahydrofuran; dimethylformamide andthe like.

As used herein, “a phase transfer catalyst” is any catalyst that willdissolve in a two-phase liquid system and enhance the rate of reactionbetween a reactant in an aqueous phase and one in an organic phase. Awide variety of phase transfer catalysts are known in the art including,but not limited to, quaternary ammonium or phosphonium salts, crownethers, and glycols.

As used herein, “methylphenidate” refers to a compound having thefollowing general formula (I):

wherein R₁ represents a phenyl group. Methylphenidate has four differentstereoisomers:

wherein R₁ represents phenyl.

As used herein, “d-threo-methylphenidate” is intended to mean thed-threo stereoisomer of methylphenidate, which can also be referred toherein as dexmethylphenidate or (2R,2′R)-(+)-methylphenidate.d-threo-methylphenidate has the following chemical structure:

The present invention provides methods for preparing a substantiallypure d-threo stereoisomer of methylphenidate or a salt thereof, andpreferably substantially pure d-threo-methylphenidate hydrochloride.

In one general aspect, the present invention provides a method forpreparing a substantially pure d-threo stereoisomer of methylphenidaterepresented by formula (I):

or a salt thereof represented by formula (I-a):

wherein R₁ is a phenyl group, and X represents fluorine, chlorine,bromine, iodine, or tetrafluoroborate. A method according to the presentinvention comprises reacting a substantially pure d-threo ritalinic acidrepresented by formula (II):

or a salt thereof represented by formula (II-a):

with diazomethane, wherein X and R₁ are defined as above.

Diazomethane, which can be abbreviated as CH₂N₂, is a methylatingreagent used to convert carboxylic acids to methyl esters. It is alsoused as a methylating reagent for other functional groups, such asphenols, alcohols, and heteroatoms, and for ring expansion or chainextension of ketones. Thus, diazomethane has utility in a wide range ofchemical syntheses. However, diazomethane is highly explosive and highlytoxic, which limits its use in the production of compounds on a largescale. Thus, despite its applicability in chemical synthesis,diazomethane is often only employed in small scale reactions when it canbe used under dilute conditions. In the present invention, it has beendiscovered that diazomethane can be used in large scale reactions toproduce large quantities of a substantially pure d-threo stereoisomer ofmethylphenidate represented by formula (I), or a salt thereofrepresented by formula (I-a), and in particular, large quantities ofsubstantially pure d-threo-methylphenidate hydrochloride in a singlebatch production.

A method for producing a substantially pure d-threo stereoisomer ofmethylphenidate by reacting a substantially pure d-threo stereoisomer ofritalinic acid with diazomethane according to embodiments of the presentinvention is depicted in Scheme 1 below. A method for producing a saltof a substantially pure d-threo stereoisomer of methylphenidate byreacting a salt of a substantially pure d-threo stereoisomer ofritalinic acid with diazomethane according to embodiments of the presentinvention is depicted in Scheme 2 below.

According to embodiments of the present invention, diazomethane can beprepared by any method known in the art and described herein. Forexample, methods for preparing diazomethane are described in U.S. Pat.Nos. 5,854,405 and 5,817,778, which are incorporated herein by referencein their entirety.

In one embodiment, diazomethane for use in the present invention isprepared by adding a solution of an N-methyl-N-nitroso amine of formula(IV):

in a water immiscible organic solvent to an aqueous solution comprisingan inorganic base and a water miscible solvent, wherein R₂ represents amember selected from the group consisting of consisting of:

R₃ represents a hydrogen atom, an alkyl group having one to four carbonatoms, or a nitro group; and R₄ represents a hydrogen atom or an alkylgroup having one to four carbon atoms.

Examples of N-methyl-N-nitroso amines of formula (IV) that can be usedwith the present invention include, but are not limited to,N-methyl-N-nitrosurea, N,N′-dimethyl-N-nitrosurea,N-methyl-N′-nitro-N-nitrosurea, N-methyl-N-nitrosoguanidine,N,N′-dimethyl-N-nitrosoguanidine, N-methyl-N′-nitrosoguanidine,N-methyl-N-nitrosocarbamic acid, N-methyl-N-nitrosocarbamate, methylN-methyl-N-nitrosocarbamate, ethyl N-methyl-N-nitrosocarbamate, andN-methyl-N-nitroso-p-toluenesulfonamide.

In a preferred embodiment, the N-methyl-N-nitroso amine of formula (IV)is N-methyl-N-nitroso-p-toluenesulfonamide.N-methyl-N-nitroso-p-toluenesulfonamide can by synthesized according toany method known in the art or it can be obtained from commercialsources, e.g., Sigma-Aldrich, which sellsN-methyl-N-nitroso-p-toluenesulfonamide under the trade name DIAZALD®.The N-methyl-N-nitroso amine of formula (IV) is prepared as a solutionin a water immiscible organic solvent. The water immiscible organicsolvent is preferably one that will co-distill with the diazomethanethat is produced to decrease the risk of accumulating a highconcentration of diazomethane in the vapor phase. In this way, theconcentration of diazomethane can be kept below non-explosive levels.Examples of such water immiscible organic solvents include, but are notlimited to ethers, diethers, alkanes and hydrocarbon mixtures such aspetroleum ethers with boiling temperatures below about 50° C. Preferablythe water immiscible organic solvent is an ether solvent, morepreferably an ether solvent with a boiling point less than about 40° C.,and most preferably is diethyl ether.

According to embodiments of the present invention, a solution of anN-methyl-N-nitroso amine of formula (IV) is prepared in the waterimmiscible organic solvent. The solution containing theN-methyl-N-nitroso amine is then added at a controlled rate to anaqueous solution comprising an inorganic base and a water misciblesolvent. The rate at which the solution containing theN-methyl-N-nitroso amine is added to the aqueous solution is determinedbased upon the particular reaction parameters including theconcentration of N-methyl-N-nitroso amine in the water-immiscibleorganic solvent, the specific water-immiscible organic solvent that isused, and the concentration of base in the aqueous solution.

The inorganic base in the aqueous solution is not limited in any way andcan be, for example, an alkali metal hydroxide, such as lithiumhydroxide, sodium hydroxide, and potassium hydroxide. A preferredinorganic base is potassium hydroxide.

According to embodiments of the present invention, a phase transfercatalyst can be included in the aqueous solution comprising theinorganic base and the water miscible solvent. The phase transfercatalyst can be any phase transfer catalyst known in the art anddescribed herein. For example, the phase transfer catalyst can beselected from quaternary ammonium salts, quaternary phosphonium salts,crown ethers and glycol ethers. Preferably, the phase transfer catalysthas a high boiling point and does not undergo chemical decomposition orevaporate into the vapor phase under the conditions used generate thediazomethane, which is under basic conditions at temperatures most oftengreater than 45° C. Examples of quaternary ammonium salts suitable foruse in the present include benzyltriethylammonium chloride,methyltrioctylammonium chloride, methyltrioctylammonium bromide,tetra-n-butylammonium chloride, and tetra-n-butylammonium bromide.Examples of quaternary phosphonium salts suitable for use in the presentinvention include tetra-n-butylphosphonium chloride andtetra-n-butyl-phosphonium bromide. Examples of crown ethers suitable foruse in the present invention include hexaoxacyclooctodecane. Preferredphase transfer catalysts include glycol ethers, such as diethyleneglycol monomethyl ether, diethylene glycol monoethyl ether, triethyleneglycol monomethyl ether, and triethylene glycol monomethyl ether, and ismost preferably diethylene glycol monoethyl ether.

According to embodiments of the present invention, when a phase transfercatalyst is included in the aqueous solution comprising the inorganicbase and the water miscible solvent, a catalytic amount of phasetransfer catalyst is used in a method of the present invention. One ofordinary skill in the art would understand was it meant by a catalyticamount, and that a catalytic amount of a particular reagent will varydepending on the amounts of other reagents in the reaction. Determininga catalytic amount of a phase transfer catalyst to be used in a methodof the present invention is well within the skill level of the ordinaryartisan in view of the present disclosure.

In some embodiments of the present invention, the aqueous solution canfurther comprise a water immiscible organic solvent, which can be thesame as or different from, the water immiscible organic solvent used inthe solution containing the N-methyl-N-nitroso amine compound.Preferably, when an aqueous solution further comprises a waterimmiscible organic solvent, it is the same water immiscible organicsolvent as that in the N-methyl-N-nitroso amine solution.

According to embodiments of the present invention, while adding thesolution of the N-methyl-N-nitroso amine of formula (IV) to the aqueoussolution, the aqueous solution is maintained at a temperature sufficientto vaporize the water immiscible organic solvent and the diazomethanethat is formed. Diazomethane is a gas at room temperature and condensesto the liquid phase at a temperature of about −23° C. The concentrationof N-methyl-N-nitroso amine in the water immiscible organic solvent,concentration of inorganic base in the aqueous solution, temperature ofthe aqueous solution, and rate of addition of the solution containingthe N-methyl-N-nitroso amine to the aqueous solution are adjustedaccordingly to control the production of diazomethane, such that theamount of diazomethane in both the vapor and liquid phases is limited toa non-explosive level.

According to embodiments of the present invention, the concentration ofN-methyl-N-nitroso amine in the water immiscible organic solvent isapproximately 20% by weight. Preferably, the concentrations of theN-methyl-N-nitroso amine and inorganic base in the starting solutions,temperature of the aqueous solution, and rate of addition are selectedsuch that the concentration of diazomethane does not exceed 3 percent byweight in the liquid phase, and 25 percent by volume in the vapor phase.For example, the concentration of diazomethane in the liquid phase canbe 0.5%, 1%, 1.5%, 2%, 2.5% or 3% by weight, and the concentration ofdiazomethane in the vapor phase can be 15%, 16%, 17%, 18%, 19%, 20%,21%, 22%, 23%, 24% or 25% by volume. Preferably, the concentration ofdiazomethane in the vapor phase is between 15% and 25% by volume.

According to embodiments of the present invention, the temperature ofthe aqueous solution is maintained at about 45° C. to about 55° C., andpreferably at about 48° C. to about 53° C.

According to other embodiments, the concentration of theN-methyl-N-nitroso amine in the water immiscible organic solvent can beabout 15 mol % to about 30 mol %, and the concentration of the inorganicbase in the aqueous solution can be about 40 mol % to about 50 mol %.

The rate of addition of the solution of the N-methyl-nitroso amine inthe water immiscible organic solvent to the aqueous solution of theinorganic base is adjusted to control the amount of diazomethaneproduced. According to embodiments of the present invention the rate ofaddition of the N-methyl-nitroso amine in the water immiscible organicsolvent to the aqueous solution of the inorganic base is performed at arate to meet all safety requirements when generating diazomethane, e.g.,the condenser for isolating diazomethane is preferably maintained at<30° C., and addition is slow so as not to generate excess N₂ gas andpressurize the equipment. According to embodiments of the presentinvention, upon adding the solution of N-methyl-N-nitroso amine in thewater immiscible organic solvent to the aqueous solution of theinorganic base and water miscible solvent, diazomethane is vaporizedalong with the water immiscible organic solvent, providing a vaporphase. The vapor phase, which contains diazomethane, is then condensedto liquid form. Preferably, once the vapor phase is condensed to liquidform, the concentration of diazomethane in the liquid form does notexceed 40 mol % by weight. Once diazomethane is condensed into liquidform, the diazomethane can be reacted with a substantially pure d-threostereoisomer of ritalinic acid represented by formula (II) or a saltthereof represented by formula (II-a). Moreover, the amount of waterimmiscible solvent distilled with the diazomethane can be varied tocontrol the rate of reaction of diazomethane with the d-threostereoisomer of ritalinic acid. For example, increasing the amount ofwater immiscible solvent will decrease the reaction rate.

According to embodiments of the present invention, the vapor phasecontaining diazomethane is condensed to the liquid phase at atemperature of about −22° C., and preferably at a temperature below −22°C., to about 15° C. The temperature over the course of distillation canvary. For example, at the start of distillation, the temperature ispreferably below −22° C., but as the distillation continues thetemperature can increase up to about 15° C. Once distillation iscomplete and the distillate containing diazomethane is collected, thediazomethane can be reacted with a substantially pure d-threostereoisomer of ritalinic acid represented by formula (II) or a saltthereof represented by formula (II-a).

According to embodiments of the present invention, a substantially pured-threo stereoisomer of ritalinic acid of formula (II) or a salt thereofof formula (II-a) that is in solution is mixed with a solvent that isinert to diazomethane, i.e., does not react with diazomethane, such asethyl acetate. Preferably, the solvent is ethyl acetate.

In a preferred embodiment, the vapor phase containing diazomethane iscondensed directly into a solution of a substantially pure d-threostereoisomer of ritalinic acid of formula (II) or a salt thereof offormula (II-a). According to this embodiment, the temperature of thesolution containing the substantially pure d-threo stereoisomer ofritalinic acid represented by formula (II) or salt thereof of formula(II-a) is initially maintained at a temperature of about −22° C. toabout 15° C. to facilitate condensation of the vapor phase, andpreferably, the temperature at the start of condensation is below −22°C. Upon completion of distillate collection, the temperature of thesolution can then be increased to a temperature at which thediazomethane will react with the substantially pure d-threo stereoisomerof ritalinic acid represented by formula (II) or salt thereofrepresented by formula (II-a).

The starting material employed in a method of the present invention is asubstantially pure d-threo stereoisomer of ritalinic acid represented byformula (II), or a salt thereof represented by formula (II-a), meaningthat the ritalinic acid or salt thereof is substantially free of any1-threo, d-erythro, and 1-erythro stereoisomers of the compound offormula (II). It is preferable that the salt of the substantially pured-threo stereoisomer of ritalinic acid represented by formula (II) is99% pure, and more preferably 99.9% pure or greater, meaning that nomore than 0.1 to 1% of the compound of formula (II), and preferably nomore than 0.01% to 0.1% is present in a stereoisomeric form other thanthe d-threo form as determined by high performance liquid chromatography(HPLC) analysis.

According to embodiments of the present invention, approximately 4 to 9molar equivalents of diazomethane relative to the substantially pured-threo stereoisomer of ritalinic acid represented by formula (II) orsalt thereof of formula (II-a) are employed in a method of the presentinvention. For example, 4, 5, 6, 7, 8, or 9 molar equivalents ofdiazomethane can be used. In a preferred embodiment, approximately 4molar equivalents of diazomethane are used.

According to embodiments of the present invention, a reaction of asubstantially pure d-threo stereoisomer of ritalinic acid represented byformula (II) or salt thereof of formula (II-a) with diazomethane isperformed at a temperature of about −20° C. to 10° C., and preferably ata temperature of about 10° C. During the course of the reaction, thereaction mixture can be stirred or agitated using any technique known inthe art, and can proceed until the reaction between diazomethane and thesubstantially pure d-threo stereoisomer of ritalinic acid represented byformula (II) or salt thereof of formula (II-a) is complete. One ofordinary skill in the art would readily be able to determine when thereaction is complete by, for example, thin layer chromatography (TLC)analysis, etc. in view of the present disclosure For example, thereaction can be considered complete when approximately 90% of theritalinic acid of formula (II) is converted to the compound of formula(I). Preferably, the reaction mixture is stirred for a period of about12 hours, and more preferably is stirred for a period of about 12 hoursat a temperature of about 10° C.

Once the reaction is complete, the substantially pure d-threostereoisomer of methylphenidate represented by formula (I) or saltthereof of formula (I-a) can be recovered from the reaction mixture.Methods for recovering the compound from the reaction mixture are notparticularly limited, and any method known in the art can be used toisolate the compound, such as distillation, filtration, crystallization,precipitation, etc. For example, the reaction can be quenched with acid,followed by distillation to remove volatile organic solvents. Theremaining solution can then be filtered, followed by the addition ofhydrochloric acid to the filtrate to precipitate the substantially pured-threo stereoisomer of methylphenidate represented by formula (I) orsalt thereof of formula (I-a) as a solid. The solid containing thesubstantially pure d-threo stereoisomer of methylphenidate representedby formula (I) or salt thereof of formula (I-a) can be filtered, washedand dried. One of ordinary skill in the art will readily be able todetermine and employ the appropriate techniques for recovering asubstantially pure d-threo stereoisomer of methylphenidate representedby formula (I) or salt thereof of formula (I-a) from the reactionmixture in order to maximize compound yield, purity, etc.

According to embodiments of the present invention, upon completion ofthe reaction of diazomethane with the substantially pure d-threostereoisomer of ritalinic acid represented by formula (II) or saltthereof of formula (II-a), any remaining diazomethane can be destroyedand rendered innocuous by the addition of an acid, preferably an organicacid, to liberate nitrogen and methyl compounds. A preferred organicacid for this purpose is acetic acid.

According to a preferred embodiment of the present invention, in a saltof a substantially pure d-threo stereoisomer of methylphenidaterepresented by formula (I-a), and a salt of a substantially pure d-threostereoisomer of ritalinic acid represented by formula (II-a), X ischlorine.

According to embodiments of the present invention, a salt of asubstantially pure d-threo stereoisomer of methylphenidate representedby formula (I-a) can be converted to any other salt using any methodknown in the art in view of the present disclosure. For example, when Xis other than chlorine, the salt of the substantially pure d-threostereoisomer of methylphenidate represented by formula (I-a) can beconverted to substantially pure d-threo methylphenidate hydrochlorideby, e.g., reacting the salt of methylphenidate with HCl.

In another general aspect, the present invention provides a method forpreparing substantially pure d-threo-methylphenidate hydrochloride.d-threo-methylphenidate hydrochloride is a representative compound offormula (I-a), wherein X is chlorine and R¹ is a phenyl group.

According to embodiments of the present of the present invention, themethod comprises reacting substantially pure d-threo-ritalinic acidhydrochloride with diazomethane. Any method described herein forobtaining diazomethane can be used in a method for producingsubstantially pure d-threo-methylphenidate hydrochloride according tothe invention.

d-threo-ritalinic acid hydrochloride is a representative compound offormula (II-a), wherein X is chlorine and R₁ is a phenyl group.d-threo-ritalinic acid hydrochloride has the following chemicalstructure:

d-threo-ritalinic acid hydrochloride for use in a method of the presentinvention can be obtained from a commercial source, or it can beobtained using any preparation method known in the art. For example,d-threo-ritalinic acid hydrochloride is commercially available fromMalladi Drugs & Pharmaceuticals, Ltd.

According to embodiments of the present invention, d-threo ritalinicacid hydrochloride employed as starting material is substantially freeof any 1-threo, d-erythro, and 1-erythro stereoisomers of ritalinicacid. It is preferable that the substantially pure d-threo-ritalinicacid hydrochloride be 99% pure, and more preferably 99.9% pure or more,meaning that no more than 0.1% to 1%, and preferably no more than 0.01%to 0.1%, of the ritalinic acid hydrochloride is present in astereoisomeric form other than the d-threo form.

A method for producing substantially pure d-threo-methylphenidatehydrochloride by reacting substantially pure d-threo-ritalinic acidhydrochloride with diazomethane according to embodiments of the presentinvention is depicted in Scheme 3 below.

According to embodiments of the present invention, a method forpreparing substantially pure d-threo-methylphenidate hydrochloridecomprises obtaining a first solution comprising an aqueous solution ofan inorganic base and a water miscible solvent, obtaining a secondsolution comprising an N-methyl-N-nitroso amine of formula (IV) in awater immiscible organic solvent, and adding the second solution to thefirst solution to generate diazomethane. The diazomethane that isgenerated is subsequently reacted with substantially pured-threo-ritalinic acid hydrochloride, thereby producing substantiallypure d-threo-methylphenidate hydrochloride.

Any of the reaction conditions, parameters, etc., described herein for amethod of preparing a substantially pure d-threo stereoisomer ofmethylphenidate represented by formula (I) or a salt thereof representedby formula (I-a) can be used in method according to the invention forpreparing substantially pure d-threo-methylphenidate hydrochloride.

In a preferred embodiment of the present invention, a first solutioncomprises an aqueous solution of potassium hydroxide. In anotherpreferred embodiment, the water immiscible organic solvent in the secondsolution is an ether solvent, preferably diethyl ether.

Until now, production of methylphenidate in both stereoisomerically pureform and in large quantities has been limited due to the need to purifythe desired stereoisomer from a mixture of stereoisomers byrecrystallization, for example, or due to synthetic procedures requiringa large number of steps, with a loss in product yield occurring at eachstep. Methods according to the present invention satisfy the need for amethod that provides a substantially pure d-threo stereoisomer ofmethylphenidate in both pure stereoisomeric form and in largequantities. This is at least because a method according to the presentinvention utilizes a stereoisomerically pure starting material directlyin a reaction that can be performed on a large scale. In a particularlypreferred embodiment, substantially pure d-threo-methylphenidatehydrochloride can be produced by a method according to the presentinvention in both pure stereoisomeric form and in large quantities froma single reaction.

As used herein, in one embodiment, a reaction performed on “a largescale” or “a large scale reaction” is intended to mean a reaction thatemploys at least 300 grams of a substantially pure d-threo stereoisomerof ritalinic acid represented by formula (II) or a salt thereof offormula (II-a) as starting material per batch reaction. For example, atleast 300, 400, 500, 600, 700, 800, 900 or 1000 grams or more of thesubstantially pure d-threo stereoisomer of ritalinic acid represented byformula (II) can be used as starting material. More preferably, a methodaccording to the present invention is performed on a kilogram scale,wherein at least 1 kilogram of the substantially pure d-threostereoisomer of ritalinic acid represented by formula (II) or saltthereof of formula (II-a) is used as starting material.

“Batch reaction,” as used herein, has its broadest reasonable meaning asknown in the art, and broadly refers to any reaction, wherein apredetermined amount of at least one reagent is added to the reaction ata particular rate of addition. In one embodiment, a “batch reaction”refers to a reaction, wherein a predetermined amount of a solution of anN-methyl-N-nitroso amine of formula (IV) in a water immiscible organicsolvent is added to a solution comprising an aqueous solution of aninorganic base and a water miscible solvent to generate diazomethane,which can react with a substantially pure d-threo stereoisomer ofritalinic acid represented by formula (II) or a salt thereof of formula(II-a) to produce a substantially pure d-threo stereoisomer ofmethylphenidate of formula (I) or a salt thereof of formula (I-a). Inanother embodiment, a “batch reaction” refers to a reaction, wherein apredetermined amount of a solution of an N-methyl-N-nitroso amine offormula (IV) in a water immiscible organic solvent is added to asolution comprising an aqueous solution of an inorganic base and a watermiscible solvent to generate diazomethane, which can react withsubstantially pure d-threo ritalinic acid hydrochloride to producesubstantially pure d-threo methylphenidate hydrochloride.

In other embodiments, a reaction performed on “a large scale” or “alarge scale reaction” refers to a reaction, wherein at least 200 gramsof a substantially pure d-threo stereoisomer of methylphenidaterepresented by formula (I) or salt thereof of formula (I-a) is producedby a method of the present invention per batch reaction. For example, atleast 200, 300, 400, 500, 600, 700, 800, or 900 grams or more of asubstantially pure d-threo stereoisomer of methylphenidate representedby formula (I) or salt thereof of formula (I-a) can be produced by amethod of the present invention per batch reaction.

In particularly preferred embodiments, at least 300 grams ofsubstantially pure d-threo-ritalinic acid hydrochloride is used asstarting material in a method of the present invention per batchreaction, such as 300, 400, 500, 600, 700, 800, 900 or 1000 grams ormore per batch reaction. More preferably at least 1000 grams ofsubstantially pure d-threo-ritalinic acid hydrochloride is utilized asstarting material per batch reaction. Preferably, at least 200 grams ofsubstantially pure d-threo-methylphenidate hydrochloride are produced bya method of the present invention per batch reaction.

The present inventors have also found that direct utilization of thehydrochloride salt of substantially pure d-threo-ritalinic acid in amethod of the present invention enables high-throughput synthesis andmanufacturing of d-threo methylphenidate hydrochloride that is more costeffective and can be more efficiently scaled-up. Methylphenidatehydrochloride (d-threo stereoisomer) is the approved activepharmaceutical ingredient (API) for the treatment of neurologicaldisorders, e.g., attention deficit hyperactivity disorder (ADHD). Thus,by using the hydrochloride salt of d-threo ritalinic acid in a method ofthe present invention, the API can be obtained directly, therebyeliminating additional synthetic steps that would otherwise be necessaryto obtain the hydrochloride salt, e.g., conversion to free base,reaction with HCl, etc.

Another general aspect of the present invention provides a system forproducing a substantially pure d-threo stereoisomer of methylphenidaterepresented by formula (I) or a salt thereof of formula (I-a). Accordingto embodiments of the present invention, a system comprises (i) areaction chamber comprising a generator portion and a receiver portion,and (ii) a solution of an N-methyl-N-nitroso amine of formula (IV) in awater immiscible organic solvent.

According to embodiments of the present invention, the generator portioncomprises an inlet. The inlet can be of any size and shape, and can belocated anywhere on the generator portion, so long as the inlet allowsfor the introduction of the solution of the N-methyl-N-nitroso amine offormula (IV) into the generator portion. The generator portion holds anaqueous solution comprising an inorganic base and a water misciblesolvent. Any inorganic base disclosed herein can be used. Preferably,the inorganic base is potassium hydroxide.

The generator portion is maintained at a temperature sufficient tovaporize the water immiscible organic solvent and the diazomethane thatis generated upon introduction of the N-methyl-N-nitroso amine offormula (IV) into the generator portion. The temperature of thegenerator portion is maintained at a temperature of about 45° C. toabout 55° C., and preferably at temperature of about 48° C. to about 53°C.

According to embodiments of the present invention, the receiver portionis connected to the generator portion by a condenser. The condenser ismaintained at a temperature that facilitates condensation of the vaporphase containing diazomethane and the water immiscible organic solvent.The condenser is maintained at a temperature of about −22° C. to about15° C., and is more preferably maintained at a temperature below −22° C.at least at the start of distillation.

The receiver portion holds a substantially pure d-threo stereoisomer ofritalinic acid represented by formula (II) or a salt thereof of formula(II-a). Preferably, the substantially pure d-threo stereoisomer ofritalinic acid or salt thereof is in solution, and is more preferably ina solution of ethyl acetate. The temperature at which the receiverportion is maintained is variable, and can be adjusted depending uponwhich step of the method is being performed. For example, during thegeneration of diazomethane, wherein the solution containing theN-methyl-N-nitroso amine of formula (IV) in a water immiscible organicsolvent is being fed into the generator portion via the inlet to producediazomethane, the receiver portion is maintained at a temperature thatfacilitates condensation of the vapor phase, such that the distillate iscollected in the receiver portion. During this stage of the method, thetemperature of the receiver portion is preferably maintained at about−22° C. to about 15° C., and preferably below about −22° C. at least atthe start of distillation. In a particularly preferred embodiment, thereceiver portion at this stage is maintained at temperature that issubstantially equivalent to the temperature at which the condenser ismaintained. However, once collection of the distillate in the receiverportion is complete, the temperature of the receiver portion can beadjusted to a temperature that promotes the reaction of diazomethanewith the substantially pure d-threo stereoisomer of ritalinic acid offormula (II) or salt thereof of formula (II-a), such as, for example,about 10° C.

Any of the methods for producing a substantially pure d-threostereoisomer of methylphenidate of formula (I) or salt thereof offormula (I-a), or for producing substantially pured-threo-methylphenidate hydrochloride described herein can be performedusing a system according to the present invention. A system according tothe present invention allows for diazomethane to be used directly in amethod of the present invention as soon as it is generated.

The inventors of the present invention have surprisingly discovered thatupon reacting a salt of a substantially pure d-threo stereoisomer ofritalinic acid represented by formula (II-a) with diazomethane toproduce a salt of a substantially pure d-threo-stereoisomer ofmethylphenidate represented by formula (I-a) according to a method ofthe present invention, an N-methyl species of the d-threo stereoisomerof methylphenidate represented by formula (I) having the followingformula (III) is also obtained:

wherein R₁ represents a phenyl group.

Likewise, upon reacting substantially pure d-threo-ritalinic acidhydrochloride with diazomethane to produce substantially pured-threo-methylphenidate hydrochloride, an N-methyl species ofd-threo-methylphenidate hydrochloride is also produced having the aboveformula (III), wherein R₁ represents a phenyl group is also obtained.This was a surprising effect of the present invention becausediazomethane is typically not known to methylate the nitrogen atom of apiperidine moiety. Without wishing to be bound by any theories, it isbelieved that formation of the N-methyl species can be produced upon areaction with, e.g., methyl chloride. The methyl chloride is believed tobe produced from a reaction of diazomethane with d-threo ritalinic acidhydrochloride.

According to embodiments of the present invention, in a method forproducing a substantially pure d-threo stereoisomer of methylphenidateor salt thereof, an N-methyl species represented by formula (III) isproduced in an amount that is about 5% to 8% by area based on peak areaof a peak corresponding to the N-methyl species as determined by highperformance liquid chromatography (HPLC) analysis, and preferably 5%area of less, relative to a total of 100% area based on peak area ofpeaks corresponding to the substantially pure d-threo stereoisomer ofmethylphenidate or salt thereof and the N-methyl species of formula(III) as determined by HPLC analysis. For example, the N-methyl speciesof formula (III) is produced in an amount that is about 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5% 0.4%, 0.3%, 0.2%, 0.1% area or less, based on thearea of the peak corresponding to the N-methyl species of formula (III)relative to the total area of the peaks corresponding to the N-methylspecies of formula (III) and the substantially pure d-threo stereoisomerof methylphenidate or salt thereof as determined by HPLC analysis.

According to another preferred embodiment of the present invention, in amethod for producing substantially pure d-threo-methylphenidatehydrochloride, an N-methyl species thereof is produced in an amount thatis about 5% to 8% area based on a peak area corresponding to theN-methyl species, and preferably 5% area or less, relative to a total of100% area based on peak area of peaks corresponding to the substantiallypure d-threo-methylphenidate hydrochloride and the N-methyl speciesthereof as determined by HPLC analysis. For example, the N-methylspecies is produced in an amount that is about 8%, 7%, 6%, 5%, 4%, 3%,2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% area or less based on the area ofthe peak corresponding to the N-methyl species relative to the totalarea of the peaks corresponding to the N-methyl species and thesubstantially pure d-threo-methylphenidate hydrochloride as determinedby high performance liquid chromatography (HPLC) analysis.

A substantially pure d-threo-stereoisomer of methylphenidate representedby formula (I) or a salt thereof of formula (I-a) produced according toa method of the present invention can be purified to remove any N-methylspecies of formula (III) by any method known in the art for purifyingchemical compounds. For example, the salt of the substantially pured-threo-stereoisomer of methylphenidate represented by formula (I-a) canbe separated from the N-methyl species of formula (III) by washing witha mixture of isopropyl acetate/acetone. As another illustrative example,addition of stoichiometric amounts of hydrochloric acid to form thehydrochloride salt of the substantially pure d-threo-stereoisomer ofmethylphenidate represented by formula (I) can be used as a method forpurifying away the N-methyl species thereof. Thus, a method according toan embodiment of the present invention further comprises separating thesubstantially pure d-threo-stereoisomer of methylphenidate of formula(I) or salt thereof of formula (I-a) from the N-methyl species thereof

In a preferred embodiment, a substantially pure d-threo stereoisomer ofmethylphenidate represented by formula (I) or salt thereof representedby formula (I-a) produced according to a method of the present inventioncontains no more than 0.10% of the N-methyl species.

In another aspect, the present invention relates to a compositioncomprising a pharmaceutically acceptable salt of substantially pured-threo methylphenidate hydrochloride, and an N-methyl species ofd-threo methylphenidate hydrochloride.

According to embodiments of the present invention, substantially pured-threo methylphenidate hydrochloride and the N-methyl species thereofin a composition of the present invention are obtained by a methodaccording to the present invention for preparing substantially pured-threo methylphenidate hydrochloride by reacting substantially pured-threo ritalinic acid hydrochloride with diazomethane.

In a preferred embodiment, a composition according to the inventioncomprises substantially pure d-threo-methylphenidate hydrochloride andan N-methyl species of d-threo-methylphenidate hydrochloride, whereinthe N-methyl species is present in an amount that is no more than 0.10%area based on peak area as determined by HPLC analysis relative to atotal of 100% area based peak area of peaks corresponding to thesubstantially pure d-threo methylphenidate hydrochloride and theN-methyl species thereof. For example, the N-methyl species is presentin an amount that is 0.10%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.01%,0.001% area or less.

The following examples of methods for preparing a salt of asubstantially pure d-threo stereoisomer of methylphenidate representedby formula (I) according to embodiments of the present invention are tofurther illustrate the nature of the invention. It should be understoodthat the following examples do not limit the invention and that thescope of the invention is to be determined by the appended claims.

EXAMPLES

The following abbreviations are used in the following examples, unlessclearly stated otherwise:

iProAc: isopropyl acetateHPLC: high performance liquid chromatographyg: gramsmol: molesS: weight equivalents of material relative to equivalents of startingmaterialS.M.: starting materiald-TRA-HCl: d-threo-ritalinic acid hydrochlorided-TRA-HBF₄: d-threo-ritalinic acid tetrafluoroboric acidTHF: tetrahydrofuranEtOAc: ethyl acetateEt₂O: diethyl etherR.T. reaction temperature

Example 1 Preparation of d-Threo-Methylphenidate Hydrochloride fromd-Threo-Ritalinic Acid Hydrochloride Using Diazomethane

d-threo-ritalinic acid hydrochloride (10 g, 0.04 mol, 1S) was added tothe receiver portion of a reaction cell, followed by the addition ofethyl acetate (180 g, 18 S). The solution containing d-threo-ritalinicacid hydrochloride was then cooled to −20 C. In the generator portion ofthe reaction cell, 45% potassium hydroxide solution (30 g, 3S),diethylene glycol monoethyl ether (59 g, 5.9 S) and diethyl ether (5 g,0.5 S) were charged and heated to a temperature that was maintainedbetween to 48° C. to 53° C.

Separately, a diazald solution in ether was prepared (approx 26 wt %,140 g, 14 S). The diazald solution was then fed into the generator, withthe temperature maintained at a range of 48° C. to 53° C. The distillatewas collected in the receiver, with the temperature of the receivermaintained at −15° C. to −22° C. during collection of the distillate.

After collection of the distillate was complete, the receiver was heatedto 10° C. and post-stirred for 12 hours. The reaction was quenched byadding 60% acetic acid (4 g) to the receiver, maintaining thetemperature at 10° C. (˜80% conversion was observed in process). Thequenched reaction solution was vacuum distilled at ambient temperatureto remove diethyl ether until approximately 110 g (11 S) of solutionremained. The mother liquor was filtered to remove unreactedd-threo-ritalinic acid hydrochloride (approximately 2 g wet, 0.2 S). Thefiltrate was cooled down to between 0-5° C., and charged with 37%aqueous hydrochloric acid (2.70 g, 0.27 S) to precipitate solids. Theprecipitated solids were filtered and washed with a mixture of iProAc (5g, 0.5 S) and acetone (27 g, 2.7 S) until an in process sample containedno less than 99.5% of d-threo-methylphenidate hydrochloride and not morethan any unknown of 0.10%. The product was dried under vacuum at 45° C.until a constant weight was achieved (approximately 12 h). Expectedyield 76%; HPLC Purity 99.7% area. Actual yield 85.7% yield; HPLC purity99.92% area.

Example 2 Preparation of a Salt, Including the Hydrochloride Salt, of aSubstantially Pure d-Threo Stereoisomer of Methylphenidate from a Saltof Substantially Pure d-Threo Stereoisomer of Ritalinic Acid

A salt of d-threo-methylphenidate was prepared according to methods ofthe present invention by reacting a salt of d-threo-ritalinic acid withdiazomethane. The salt of d-threo-ritalinic acid used as startingmaterial, equivalents of diazomethane, initial reaction temperature,final reaction temperature and reaction time, and solvent were varied,as detailed below in Table 1. Reactions were carried out as described inExample 1.

TABLE 1 Summary of reactions to produce d-threo-methylphenidate byreaction d-threo-ritalinic acid with diazomethane. Initial Final % AUC³Scale CH₂N₂ R.T. R.T. Reaction N-methyl Yield² S.M.¹ (g) Solvent Equiv.(° C.) (° C.) Time formed (%) d-TRA-HCl 0.1 EtOAc 3 −38.1 Room temp.overnight  n.i.⁴ n.i. d-TRA-HCl 0.1 EtOAc 6 −38.1 Room temp. Overnightn.i. n.i. d-TRA-HCl 0.1 EtOAc 9 −38.1 Room temp. overnight n.i. n.i.d-TRA-HCl 0.1 EtOAc 1 −35 Room temp. overnight n.i. n.i. d-TRA-HCl 0.1EtOAc 2 −35 Room temp. overnight n.i. n.i. d-TRA-HCl 0.1 EtOAc 3 −35Room temp. overnight n.i. n.i. d-TRA-HCl 0.1 EtOAc 1 −30.1 0 1.5 h  aq.⁵n.i. d-TRA-HCl 0.1 EtOAc 2 −30.1 0 1.5 h aq. n.i. d-TRA-HCl 0.1 EtOAc 3−30.1 0 1.5 h aq. n.i. d-TRA-HCl 0.1 EtOAc 1 −35.2 10 2 h 16 min 0.70n.i. d-TRA-HCl 0.1 EtOAc 2 −35.2 10 2 h 16 min 1.40 n.i. d-TRA-HCl 0.1EtOAc 3 −35.2 10 2 h 16 min 7.90 n.i. d-TRA-HCl 0.1 EtOAc 4 −61.7 5.61.5 h 2.2 n.i. d-TRA-HCl 0.1 EtOAc 5 −61.7 5.6 1.5 h 0.10 n.i.d-TRA-HBF₄ 0.1 EtOAc 3 −61.7 5.6 1.5 h 11.6 n.i. d-TRA-HBF₄ 0.1 EtOAc0.5 −24 2.8 1.5 h 3.4 n.i. d-TRA-HBF₄ 0.1 EtOAc 1 −24 2.8 1.5 h 1.30n.i. d-TRA-HBF₄ 0.1 EtOAc 1.5 −24 2.8 1.5 h 1.90 n.i. d-TRA-HCl 0.1EtOAc 4 −60.1 −9.9   1 h 2.74 n.i. d-TRA-HCl 0.1 THF 4 −60.1 −9.9   1 h2.31 n.i. d-TRA-HCl 0.1 Et₂O 4 −60.1 −9.9   1 h 2.12 n.i. d-TRA-HCl 20THF 4 −45 10 6.5 10.27 34   d-TRA-HCl 10 EtOAc 4 −20 10 5 4.8 76   (wet)d-TRA-HCl 10 EtOAc 4 −20 11.6 11 5.42 n/a d-TRA-HCl 10 EtOAc 4 −27 116.5 6.01 n/a d-TRA-HCl 10 EtOAc 4 −15 10 7 5.66 39.8 d-TRA-HCl 10 EtOAc4 −14 10 5 5.93 78.8 d-TRA-HCl 10 EtOAc 4 −32 13 8 4.54 63.8 d-TRA-HCl10 EtOAc 4 −20.8 14 overnight 5.7 84.8 d-TRA 0.1 EtOAc 3 −38.1 Roomtemp. overnight 1.7 n.i. d-TRA 0.1 EtOAc 6 −38.1 Room temp. overnight2.4 n.i. d-TRA 0.1 EtOAc 9 −38.1 Room temp. overnight 4.6 n.i.¹d-TRA-HCl refers to d-threo-ritalinic acid hydrochloride; d-TRA-HBF₄refers to d-threo-ritalinic acid tetrafluoroboric acid. ²Yield refers tothe total amount of methyl ester product. ³% AUC refers to percent areaunder the curve determined by HPLC analysis and is reported as area %(uncorrected)(% AUC). ⁴“n.i.” means that the species was not identifiedby the detection method employed. ⁵“a.q.” indicates that the N-methylspecies was identified in aqueous streams upon work-up of the reaction.

The results demonstrate that substantially pure d-threo methylphenidatehydrochloride can be prepared in good yield and by reaction ofsubstantially pure d-threo ritalinic acid hydrochloride withdiazomethane.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

We claim:
 1. A method for preparing a substantially pure d-threostereoisomer of methylphenidate represented by formula (I):

or a salt thereof represented by formula (I-a):

the method comprising: (i) obtaining a first solution comprising anaqueous solution of an inorganic base and a water miscible solvent; (ii)obtaining a second solution comprising an N-methyl-N-nitroso amine offormula (IV):

in a water immiscible organic solvent; (iii) adding the second solutionto the first solution, thereby generating diazomethane; and (iv)reacting a substantially pure d-threo stereoisomer of ritalinic acidrepresented by formula (II):

or a salt thereof represented by formula (II-a):

with the diazomethane generated in step (iii) to obtain thesubstantially pure d-threo stereoisomer of methylphenidate or the saltthereof, respectively, wherein R¹ represents a phenyl group; R²represents a member selected from the group consisting of

R₃ represents a hydrogen atom, an alkyl group having one to four carbonatoms, or a nitro group; R₄ represents a hydrogen atom or an alkyl grouphaving one to four carbon atoms; and X represents fluorine, chlorine,bromine, iodine, or tetrafluoroborate.
 2. The method according to claim1, wherein the salt of the substantially pure d-threo ritalinic acid isreacted with diazomethane to produce the salt of the substantially pured-threo methylphenidate, and X is chlorine.
 3. The method according toclaim 1, wherein the N-methyl-N-nitroso amine of formula (IV) isselected from the group consisting of N-methyl-N-nitrosurea,N,N′-dimethyl-N-nitrosurea, N-methyl-N′-nitro-N-nitrosurea,N-methyl-N-nitrosoguanidine, N,N′-dimethyl-N-nitrosoguanidine,N-methyl-N′-nitrosoguanidine, N-methyl-N-nitrosocarbamic acid,N-methyl-N-nitrosocarbamate, methyl N-methyl-N-nitrosocarbamate, ethylN-methyl-N-nitrosocarbamate, andN-methyl-N-nitroso-p-toluenesulfonamide.
 4. The method according toclaim 1, wherein the reaction of the substantially pure d-threostereoisomer of ritalinic acid or the salt thereof with diazomethaneproduces at least 200 grams of the substantially pure d-threostereoisomer of methylphenidate or the salt thereof per batch reaction.5. The method according to claim 1, wherein the reaction of thesubstantially pure d-threo stereoisomer of ritalinic acid or the saltthereof with diazomethane is performed in a reaction vessel comprising(a) a generator portion holding the first solution, and (b) a receiverportion holding the substantially pure d-threo stereoisomer of ritalinicacid or the salt thereof, the method comprising: (i) adding the secondsolution to the generator portion, with the generator portion beingmaintained at a temperature sufficient to vaporize the organic solventand the diazomethane that is formed, thereby obtaining a vapor phase;(ii) condensing the vapor phase in the receiver portion to obtain areaction solution; and (iii) recovering the substantially pure d-threostereoisomer of methylphenidate or the salt thereof from the reactionsolution.
 6. The method according to claim 1, wherein an N-methylspecies of the d-threo stereoisomer of methylphenidate of formula (I)represented by formula (III):

is produced in an amount of about 8% area or less based on peak area ofa peak corresponding to the N-methyl species as determined by highperformance liquid chromatography analysis relative to a total of 100%area based on peak area of peaks corresponding to the substantially pured-threo stereoisomer of methylphenidate or the salt thereof and theN-methyl species.
 7. The method according to claim 6, further comprisingseparating the substantially pure d-threo stereoisomer ofmethylphenidate or the salt thereof from the N-methyl species.
 8. Themethod according to claim 1, wherein the salt of the substantially pured-threo ritalinic acid hydrochloride is reacted with diazomethane toproduce the salt of the substantially pure d-threo methylphenidatehydrochloride and X is other than chlorine, the method furthercomprising converting the salt of the substantially pure d-threostereoisomer of methylphenidate to a hydrochloride salt of thesubstantially pure d-threo stereoisomer of methylphenidate.
 9. A methodfor preparing substantially pure d-threo-methylphenidate hydrochloride,the method comprising: (i) obtaining a first solution comprising anaqueous solution of an inorganic base and a water miscible solvent; (ii)obtaining a second solution comprising an N-methyl-N-nitroso amine offormula (IV):

in a water immiscible organic solvent; (iii) adding the second solutionto the first solution, thereby generating diazomethane; and (iv)reacting substantially pure d-threo-ritalinic acid hydrochloride withthe diazomethane generated in step (iii) to obtain the substantiallypure d-threo-methylphenidate hydrochloride, wherein R² represents amember selected from the group consisting of

R₃ represents a hydrogen atom, an alkyl group having one to four carbonatoms, or a nitro group; and R₄ represents a hydrogen atom or an alkylgroup having one to four carbon atoms.
 10. The method according to claim9, wherein the inorganic base is an alkali metal hydroxide, and thewater immiscible organic solvent is an ether.
 11. The method accordingto claim 9, wherein the reaction of substantially pure d-threo-ritalinicacid hydrochloride with diazomethane is performed in a reaction vesselcomprising (a) a generator portion holding the first solution, and (b) areceiver portion holding the substantially pure d-threo-ritalinic acidhydrochloride, the method comprising: (i) adding the second solution tothe generator portion, with the generator portion being maintained at atemperature sufficient to vaporize the organic solvent and thediazomethane that is formed, thereby obtaining a vapor phase; (ii)condensing the vapor phase in the receiver portion to obtain a reactionsolution; and (iii) recovering the substantially pured-threo-methylphenidate hydrochloride from the reaction solution. 12.The method according to claim 9, wherein the N-methyl-N-nitroso amine isselected from the group consisting of N-methyl-N-nitrosurea,N,N′-dimethyl-N-nitrosurea, N-methyl-N′-nitro-N-nitrosurea,N-methyl-N-nitrosoguanidine, N,N′-dimethyl-N-nitrosoguanidine,N-methyl-N′-nitrosoguanidine, N-methyl-N-nitrosocarbamic acid,N-methyl-N-nitrosocarbamate, methyl N-methyl-N-nitrosocarbamate, ethylN-methyl-N-nitrosocarbamate, andN-methyl-N-nitroso-p-toluenesulfonamide.
 13. The method according toclaim 9, wherein an N-methyl species of d-threo-methylphenidate isproduced in an amount of about 8% or less based on peak area of a peakcorresponding to the N-methyl species as determined by high performanceliquid chromatography analysis relative to a total of 100% area based onpeak area of peaks corresponding to the substantially pured-threo-methylphenidate hydrochloride and the N-methyl species.
 14. Themethod according to claim 13, further comprising separating the N-methylspecies from the substantially pure d-threo methylphenidatehydrochloride.
 15. The method according to claim 9, wherein the reactionof the substantially pure d-threo-ritalinic acid hydrochloride withdiazomethane produces at least 200 grams of substantially pured-threo-methylphenidate hydrochloride per batch reaction.
 16. A systemfor producing a substantially pure d-threo stereoisomer ofmethylphenidate represented by formula (I):

or a salt thereof represented by formula (I-a):

the system comprising: (i) a reaction chamber comprising: (a) agenerator portion comprising an inlet, and holding an aqueous solutioncomprising an inorganic base and a water miscible solvent, and (b) areceiver portion connected to the generator portion by a condenser, thereceiver portion holding a solution comprising a substantially pured-threo stereoisomer of ritalinic acid represented by formula (II):

or a salt thereof represented by formula (II-a):

and (ii) a solution of an N-methyl-N-nitroso amine of formula (IV):

in a water immiscible organic solvent, wherein the generator portion ismaintained at a temperature sufficient to vaporize the organic solventand any diazomethane that is formed upon introduction of the solution ofthe N-methyl-N-nitroso amine into the generator portion via the inlet;wherein R¹ represents a phenyl group; R² represents a member selectedfrom the group consisting of

R₃ represents a hydrogen atom, an alkyl group having one to four carbonatoms, or a nitro group; and R₄ represents a hydrogen atom or an alkylgroup having one to four carbon atoms; and X represents fluorine,chlorine, bromine, or tetrafluoroborate.
 17. The system according toclaim 16, wherein the receiver portions holds the salt of thesubstantially pure d-threo ritalinic acid and X is chlorine.
 18. Acomposition comprising substantially pure d-threo methylphenidatehydrochloride and an N-methyl species of d-threo-methylphenidatehydrochloride.
 19. The composition according to claim 18, wherein theN-methyl species is present in an amount that is no more than 0.10% areabased on peak area of a peak corresponding to the N-methyl species asdetermined by high performance liquid chromatography (HPLC) analysisrelative to a total of 100% area based on peak area of peakscorresponding to the substantially pure d-threo-methylphenidatehydrochloride and N-methyl species thereof as determined by HPLCanalysis.
 20. The composition according to claim 18, whereinsubstantially pure d-threo methylphenidate hydrochloride and theN-methyl species of d-threo-methylphenidate hydrochloride are obtainedby a method comprising: (i) obtaining a first solution comprising anaqueous solution of an inorganic base and a water miscible solvent; (ii)obtaining a second solution comprising an N-methyl-N-nitroso amine offormula (IV):

in a water immiscible organic solvent; (iii) adding the second solutionto the first solution, thereby generating diazomethane; and (iv)reacting substantially pure d-threo-ritalinic acid hydrochloride withthe diazomethane generated in step (iii) to obtain substantially pured-threo-methylphenidate hydrochloride, wherein R² represents a memberselected from the group consisting of

R₃ represents a hydrogen atom, an alkyl group having one to four carbonatoms, or a nitro group; and R₄ represents a hydrogen atom or an alkylgroup having one to four carbon atoms.